title: The human cathelicidin, LL-37, induces granzyme-mediated apoptosis in regulatory T cells.
abstract: LL-37 is a human cationic host defense peptide (antimicrobial peptide) belonging to the cathelicidin family of peptides. In this study, LL-37 was shown to kill stimulated and nonstimulated CD4(+)CD25(+)FoxP3(+) T cells (regulatory T cells; Tregs) through apoptosis, while having no cytotoxic effect on CD4(+)CD25(-) T cells at the same LL-37 concentrations. Of interest, Tregs were much more sensitive to LL-37 than many other cells, dying at 10-fold lower concentrations than other cell types tested. LL-37 exposure resulted in DNA fragmentation, chromatin condensation, and apoptotic body formation, all indicative of an apoptotic form of cell death. The importance of granzyme family members in the apoptosis of Tregs after LL-37 treatment was analyzed by using C57Bl/6 lymphocytes obtained from mice that were homozygous for null mutations in the granzyme B gene, and both the granzyme A and B genes. Granzyme A and granzyme B were both shown to play a role in LL-37-induced apoptosis of Tregs. Further analysis showed that apoptosis occurred primarily through caspase-dependent apoptosis at high LL-37 concentrations. However, grA-dependent/caspase-independent cell death was also observed. This suggests that LL-37 induces apoptosis in Tregs through multiple different mechanisms, initiated by the LL-37-induced leakage of granzymes from cytolytic granules. Our results imply that LL-37 administered at the site of a tumor could influence the adaptive antitumor immune response by killing Tregs and thus inhibiting their suppressor activity.
authors.affiliation: Department of Biochemistry, School of Molecular and Systems Medicine, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada. jmader@ualberta.ca
authors.forename: Jamie S
authors.initials: JS
authors.lastname: Mader
authors.forename: Catherine
authors.initials: C
authors.lastname: Ewen
authors.forename: Robert E W
authors.initials: RE
authors.lastname: Hancock
authors.forename: Robert C
authors.initials: RC
authors.lastname: Bleackley
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D000595:Amino Acid Sequence; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002843:Chromatin; D053938:DNA Fragmentation / Q000187:drug effects*; D053804:Granzymes / Q000172:deficiency* / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008213:Lymphocyte Activation; D008215:Lymphocytes, Null / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D002843:Chromatin; D053804:Granzymes; D020169:Caspases; D054804:Cathelicidins